The accumulation of proteins or protein fragments (peptides) in the brain is a significant feature of age-dependent neurodegenerative diseases. In Alzheimer's dementia (Alzheimer's disease, AD) and cerebral β-amyloidopathy (CAA) the aggregation of β-amyloid peptides (Aβ) is a trigger factor, the basic mechanism being unknown. The AR proteostasis, i.e. the equilibrium of production and degradation/removal by means of receptors or proteases is disturbed in AD and CAA. However, so far little attention has been paid to the removal of Aβ peptides by cellular transporters (ABC transporters). In Parkinson's disease, the protein α-synuclein accumulates, which inter alia regulates the dopamine release in the substantia nigra. In Parkinson's disease α-synucleinopathy it is known that ABC transporters play a crucial role for transport (Kortekaas et al., Ann Neural 2005, 57, 176-179). Here there are several subfamilies A-G which can alternatingly transport various substrates (metabolites, medicaments, peptides, proteins, ions) and are even able to replace each other in the transport function (e.g. ABCB1 and ABCC1, Tao et al. Cancer Chemotherapy and Pharmacology, 64, 5, 961-969).
It has been shown by means of various genetically modified mouse models that the ABC transporter (a common structural element of the ABC transporter is an ATP-binding cassette and a transport pore) ABCC1 is an important protein/peptide transporter, in particular Aβ transporter, which has extraordinary functional effects on the cerebral protein accumulation. ABCC1 is also an important α-synuclein transporter.
The investigations of the transporter activity are shown as an example hereinafter for Aβ transport.
In order to determine the ABCC1 activity in vivo, in APP-expressing, transgenic mice, the ABCB1, ABCG2 or ABCC1 transporter was removed genetically (knockout mice) in each case.
Here it was found that:
i) the quantity of Aβ in the mice lacking the ABCC1 transporter was increased by a factor of 12,
ii) loss of the ABCB1 transporter only results in a three-fold increase and
iii) loss of ABCG2 has no Aβ-accumulating effect.